Retracted: Deficiency of Either P-Glycoprotein or Breast Cancer Resistance Protein Protect against Acute Kidney Injury

Abstract

The kidney has a high capacity to regenerate after ischemic injury via several mechanisms, one of which involves bone marrow-derived (stem) cells. The ATP binding cassette transporters, P-glycoprotein and breast cancer resistance protein, are determinants for the enriched stem and progenitor cell fraction in bone marrow. Because they are upregulated after acute kidney injury, we hypothesized that both efflux pumps may play a role in protecting against renal injury. Surprisingly, transporter-deficient mice were protected against ischemia-induced renal injury. To further study this, bone marrow from irradiated wild-type mice was reconstituted by bone marrow from wild-type, P-glycoprotein-or breast cancer resistance protein-deficient mice. Four weeks later, kidney injury was induced and its function evaluated. Significantly more bone marrow-derived cells were detected in kidneys grafted with transporter-deficient bone marrow. A gender mismatch study suggested that cell fusion of resident tubular cells with bone marrow cells was unlikely. Renal function analyses indicated an absence of renal damage following ischemia-reperfusion in animals transplanted with transporter-deficient bone marrow. When wild-type bone marrow was transplanted in breast cancer resistance protein-deficient mice this protection is lost. Furthermore, we demonstrate that transporter-deficient bone marrow contained significantly more monocytes, granulocytes, and early outgrowth endothelial progenitor cells.

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

“…Cell fusion of resident tubular cells with bone marrow cells was unlikely to have occurred, as shown by a gender mismatch study. It is likely that the protective mechanism resulted from an altered immune reaction, since bone marrow from P-gp-or Bcrp-deficient mice contained significantly more monocytes and granulocytes as well as early outgrowth endothelial progenitor cells, (88). As these findings in ABC transporter knockout mice contradict the findings in humans with polymorphisms that lead to reduced or nonfunctional efflux pump variants, more research is essential to fully understand the renal protective mechanism in P-gp-or Bcrpdeficiency.…”

“…Contraditory reports on the involvement of SP cells in renal regeneration have been published, leaving a conclusive answer still open (88). A bone marrow reconstitution of wild-type, P-gp-or Bcrp-deficient mice origin in wild-type mice subjected to irradiation to destroy endogenous bone marrow, showed that transporter-deficient bone marrow transplantations protected wild type mice against ischemia-induced renal injury (18,88). This protection was likely a result of bone marrow-derived cells, because significantly more bone marrow-derived cells were detected in kidneys grafted with transporter-deficient bone marrow.…”

“…This indicates that Pgp and BCRP possibly determine tissue regeneration through their differential expression on SP cells, which have been implicated in the remodeling of various tissues and organs, such as skeletal muscle, liver, and heart (12). Contraditory reports on the involvement of SP cells in renal regeneration have been published, leaving a conclusive answer still open (88). A bone marrow reconstitution of wild-type, P-gp-or Bcrp-deficient mice origin in wild-type mice subjected to irradiation to destroy endogenous bone marrow, showed that transporter-deficient bone marrow transplantations protected wild type mice against ischemia-induced renal injury (18,88).…”

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

“…It is recognized that P-gp stimulates cell growth, 26 displays an antiapoptotic effect in fibroblasts, 27 promotes cholesterol ester-mediated vascular damage, 28 and is associated with increased propensity to renal injury in an animal model of ischemic injury. 29,30 This effect may relate to characteristics of reparative stem cells, which may be mobilized from (donor) bone marrow and other niches, or which may reside within the kidney itself. 31,32 Although speculative, it is plausible that these phenomena may lead to the tissue injury and disrepair that are characteristic of chronic kidney damage.…”

Stem Cells and Their Role in Renal Ischaemia Reperfusion Injury

“…They concluded that EPC pre-treatment with this integrin receptor activator augmented the anti-ischaemic potential of the cell and thus protected the kidney from acute IRI [60]. Huls et al [67] demonstrated that either p-glycoprotein (P-GP) or breast cancer-resistant protein (BCRP) protected from AKI. In the mouse model of IRI, they demonstrated absence of renal damage when animals were transplanted with transporter-deficient bone marrow SC.…”